No Higher Mortality Risk in RA With Anti-TNF Tx

Action Points

Explain to interested patients that people with rheumatoid arthritis who are treated with tumor necrosis factor (TNF) blocking agents do not appear to have an increased risk of dying compared with those on conventional disease-modifying drugs.

Note that the researchers tried to statistically adjust for the reality in clinical practice that the decision to use a TNF blocking agent is not random.

Rheumatoid arthritis patients treated with tumor necrosis factor (TNF) blocking agents do not appear to have an increased risk for mortality compared with those given conventional disease-modifying drugs, according to results from a prospective study.

During 50,803 patient-years of follow-up in the anti-TNF group, 856 of the patients died, as did 204 patients treated with conventional agents during 9,445 patient-years, reported Mark Lunt, PhD, and colleagues from the University of Manchester in England.

The overall weighted mortality hazard ratio for the anti-TNF cohort was 0.86 (95% CI 0.64 to 1.16), Lunt and co-authors wrote in the November Arthritis & Rheumatism.

The anti-TNF drugs etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) have all been shown to improve the signs and symptoms of RA, as well as to help prevent disability.

But the effects of these newer drugs on mortality are not yet known -- and are a matter of concern.

To explore mortality risks with the anti-TNF drugs after about a decade of use, Lunt's team compared the 12,672 RA patients enrolled in the British Society for Rheumatology Biologics Register and a cohort of 3,522 patients who also have active disease but were receiving nonbiologic treatments such as methotrexate.

They acknowledged, however, that an observational analysis such as theirs is challenging because of the potential for confounding by indication -- meaning that RA patients receiving TNF blockers typically have more severe disease and disability, placing them at higher risk of death.

In addition, they pointed out that an observational study also has the potential for confounding by contraindication -- meaning that RA patients with severe comorbidities may be treated with conventional drugs because of the risks of side effects and complications with anti-TNF therapy.

"Thus, the decision to treat or not to treat is not random but is based highly on a number of patient-related factors, many of which also influence the risk of death," Lunt and co-authors observed.

To account for this, the researchers used a statistical method known as inverse probability of treatment, weighting to account for potential disparities in baseline mortality risks.

Among the anti-TNF cohort, the mean age was 57, and three-quarters were women. The baseline disease activity level, as measured by the disease activity score in 28 joints (DAS28) was high, at a median of 6.6.

Baseline disability level also was high, with a median health activity questionnaire (HAQ) score of 2.1.

In the group receiving conventional therapies the median age was 61, and there were slightly more men than in the anti-TNF cohort.

Although the disease activity level among these patients was slightly lower than the anti-TNF group, it remained high -- at a median DAS28 of 5.1 -- and a median HAQ score of 1.6 indicated a moderate level of disability.

Approximately half of RA patients in both groups had comorbidities, including hypertension, chronic obstructive pulmonary disease, depression, and previous malignancy.

The researchers found that more patients in the conventional therapy group died of cancer (32% versus 20%), while more patients in the anti-TNF group died of diseases of the musculoskeletal system -- primarily severe RA (15% versus 5%).

As with the overall mortality rates, mortality risks in the anti-TNF group were not elevated for the three leading causes of death:

Circulatory disease, weighted HR 0.73 (95% CI 0.44 to 1.23)

Neoplasm, weighted HR 0.65 (95% CI 0.39 to 1.09)

Respiratory disease, weighted HR 0.81 (95% CI 0.36 to 1.83)

Strengths of the study, according to Lunt and colleagues, included its prospective design, the large number of patients, and adjustment for potential confounders.

Limitations included some missing data at baseline, such as unavailability of some HAQ scores in the nonbiologic cohort, and the lack of analysis of infection as cause of death.

The researchers also noted that different patterns of mortality may emerge with longer follow-up.

"Future analysis will confirm if this trend in mortality, including the underlying causes of death observed in both cohorts, is maintained over longer periods of follow-up," Lunt and co-authors concluded.

This project was funded by the British Society for Rheumatology, which receives restricted income from U.K. pharmaceutical companies Abbott Laboratories, Biovitrum, Schering-Plough, Wyeth Pharmaceuticals, and Roche.

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